Evaluating the Efficacy of Infliximab in Inflammatory Bowel Disease: A Systematic Review of the Literature

The introduction of steroid therapy in 1955 markedly decreased the mortality rate of severe ulcerative colitis (UC) from 24% in the placebo group to 7%, and it is currently less than 1% in specialist centers. Despite this advancement, the response of severe UC to steroids has stagnated over the past 50 years, with a high rate of colectomy persisting for severe to moderately severe cases. Infliximab (IFX) (Remicade, Centocor Inc., Malvern, PA, United States), an intravenously administered chimeric monoclonal immunoglobulin G1 antibody targeting tumor necrosis factor-alpha (TNF-α), has shown efficacy in numerous randomized controlled trials for treating moderate to severe and fistulizing Crohn's disease, particularly in patients unresponsive to conventional therapies. This led to its approval by the US Food and Drug Administration in 1998 for treating active and fistulizing Crohn's disease. Most clinical research on IFX has focused on Crohn's disease, which is characterized as a Th1-type condition driven by pro-inflammatory cytokines like TNF-α. Conversely, UC has traditionally been viewed as a Th2-type condition where TNF-α plays a lesser role. However, recent studies indicate that TNF-α might also contribute to the pathogenesis of UC. These findings highlight the necessity for larger randomized controlled trials to further investigate the benefits of therapies like IFX, with the ultimate goal of improving treatment outcomes and quality of life for patients with inflammatory bowel disease.


Introduction And Background
Inflammatory bowel disease (IBD), which encompasses Crohn's disease (CD) and ulcerative colitis (UC), is marked by chronic, relapsing inflammation of the intestines.It poses a significant global health concern because of its increasing incidence.The prevailing understanding is that IBD arises from an abnormal and persistent immune response to gut microbes, driven by the individual's genetic susceptibility.Although the exact cause of IBD remains largely elusive, it is believed to result from a complex interplay between genetic, environmental, microbial factors, and immune responses [1,2,3,4].The genetic study of gut inflammation, one of the four key components of IBD pathogenesis, has made significant advancements.Recent international collaborative studies have identified 163 gene loci associated with IBD susceptibility.Interestingly, the genetic predispositions for childhood-onset and adult-onset IBD appear to overlap, indicating similar genetic factors at play.Even though it's not clear what causes UC and CD, it is clear that immune systems become active in the inflamed mucosa, which contributes to the development of chronic diseases [4].The mucosa produces more immunoglobulins, some of which target bacterial antigens, and disease exacerbations trigger complement activation.Serum factors and bacterial antigens influence the cytotoxicity of lymphocytes isolated from both peripheral blood and intestinal mucosa to colonic epithelial cells in vitro.Within the mucosa, there is an increased presence of T lymphocytes, although the helper-tosuppressor cell ratio remains unchanged phenotypically [5].Research into immunoregulatory control has revealed potential alterations in the local immune response modulation, particularly during active disease phases.However, it remains unclear whether these changes are primary or secondary to inflammation [2,3].We hypothesize that increased antigen absorption and enhanced antigen presentation to the immune system trigger many humoral and cellular immune responses to gut-associated antigens.This is due to the expression of Class II antigens by the inflamed epithelium and altered immunoregulatory control [3,5].
Using anti-tumor necrosis factor α (anti-TNF-α) agents, like infliximab (IFX) (Remicade, Centocor Inc., Malvern, PA, United States), has proven to be clinically effective in treating patients with CD.However, the extensive use of these agents has placed a significant financial strain on healthcare systems worldwide [1,2].The significant price difference between biosimilar infliximab (CT-P13) and the original IFX for maintenance therapy highlights the financial consequences of this situation [3].Biological agents possess the ability to initiate the production of antibodies that specifically target the administered drug.This can lead to a decrease in the level of the drug in the bloodstream [4].In a significant number of patients, immunogenicity may result in primary nonresponse, heightened infusion reactions, and a decline in response over time.It is evident that there is a direct relationship between the original IFX and clinical outcomes, as higher serum levels are associated with positive results.Paul et al. did a study and found that keeping a delta IFX serum concentration above 0.5 g/mL at week eight was the only thing that was linked to endoscopic remission in people with inflammatory bowel disease (IBD).This finding had a likelihood ratio of 2.02 and a 95% confidence interval of 1.01 to 4.08, with a p-value of 0.048 [5].In the same way, Papamichael et al. found that IFX levels in the blood (≥2.2, ≥9.7, and ≥9.8 μg/mL) were related to biochemical, endoscopic, and histologic remission, in that order [6,7].
Recent consensus statements have highlighted the significance of therapeutic drug monitoring for anti-TNF-α therapy.However, depending on the clinical outcomes under assessment, the ideal drug concentrations and anti-drug antibody (ADA) thresholds may vary [6,7].In CD patients, we expect CT-P13 to exhibit comparable immunogenicity and drug concentration levels to the originator IFX [8,9].IBD patients' ADA against the original drug IFX also hinders CT-P13's function, indicating a cross-reactivity and comparable immunogenicity between these two medications.It is clear that there is a relationship between exposure to CT-P13 during the induction period and improved clinical outcomes when serum IFX levels are higher.There is a correlation between the initial IFX trough levels at week two and the effectiveness of treatment at weeks 14 and 30 in patients with UC who received CT-P13 [10].An indicator of steroid-free clinical remission and mucosal healing at week 14 was a cutoff value of 3.15 μg/mL [11].
However, studies comparing serum trough levels of CT-P13 with those of its originator have produced conflicting findings.The SECURE trial, a Phase 4 study across multiple centers, demonstrated that IBD patients who achieved clinical remission and switched to CT-P13 from the originator IFX experienced similar serum concentration and ADA levels [12,13].On the other hand, a study that looked at old data with only a few participants found that the original IFX group and the CT-P13 group had different serum IFX trough levels at week 22 in IBD patients who were not switching groups.However, it's important to note that the study's design raises questions about the accuracy of these findings.
Research has demonstrated that using a combination of IFX and azathioprine is more successful in achieving clinical remission and endoscopic healing in patients who have not previously used azathioprine.This highlights the importance of early disease management and combining treatments to improve the chances of successful treatment.Nevertheless, after achieving remission, it is crucial to thoroughly consider the advantages and disadvantages of maintaining combination therapy with IFX and an immunosuppressant (such as thiopurines or methotrexate).There is a growing consensus that the risks of serious infections and lymphoproliferative disorders are higher with combination therapy compared to monotherapy [14].It is important to be aware of these increased risks.Registry data indicate that reducing drug therapy could lower the chances of experiencing harmful drug-related side effects and potentially save money [14].However, the potential for disease relapse when stopping either or both drugs remains uncertain, as does the increased risk of immunogenicity when discontinuing immunosuppressant therapy while continuing IFX.In a randomized trial, patients who stopped immunosuppressant therapy did not experience a higher rate of treatment failure compared to those who continued combination therapy [14].The main objective of this systematic review is to comprehensively analyze recent studies on the efficacy of IFX in patients with IBD.This review aims to improve understanding of IFX treatment outcomes and provide valuable insights for effectively managing IBD through a critical evaluation of the latest research.

Review Records and Search for Studies
This systematic review followed the requirements of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [15].Independent researchers conducted exhaustive searches in Pubmed, Pubmed Central, and the Cochrane Library to choose articles.Table 1 provides details on the search methods used.

Inclusion and Exclusion Criteria
Two independent authors used the Covidence program to filter search results from two databases using predefined inclusion and exclusion criteria, as shown in Table 2.

Inclusion Exclusion
Free, full text about infliximab effectiveness Articles that do not include biological therapeutics Articles from the past 10 years Articles from 2013 and below English-language articles Non-English studies

Prospective or retrospective studies Case reports
Human trials Animal trials

TABLE 2: Inclusion and exclusion criteria
The implementation of the PICO format for the systematic review will be shown in Table 3.

Data Extraction
An exhaustive investigation of the pertinent study yielded a number of significant findings.An example of this is the design of each study, which primarily focuses on the biological treatment using infliximab in patients who have inflammatory bowel disease (IBD).

Risk of Bias Assessment
We used the Cochrane risk of bias tool, designed for randomized controlled trials (RCTs), to assess potential biases in the selected studies for our inquiry.This was conducted to assess if the studies had any potential biases.This tool has gained considerable recognition for its efficacy in assessing the quality of research that relies on case series [16].A thorough assessment of potential bias in each research piece was conducted by the reviewers, and any differences in their evaluations were resolved through meaningful discussions.

Results
After searching the PubMed, PMC, and Cochrane Library databases, a total of 2612 studies were discovered.A total of 202 studies were deemed ineligible due to inclusion and exclusion criteria, and 2013 duplicate studies were eliminated.A total of 212 studies underwent title and abstract screening, and 89 papers were discarded as they were not relevant to our study's purpose.Out of the initial pool of 123 papers, a thorough evaluation was conducted based on their English content and full-text availability over the past decade.As a result, 113 studies were excluded, leaving only 10 studies that met the criteria for the final data collection (Figure 1).VE303, a defined bacterial consortium, for prevention of recurrent Clostridioides difficile infection: a randomized clinical trial [17] 88.6 Effect of therapeutic drug monitoring vs standard therapy during maintenance infliximab therapy on disease control in patients with immune-mediated inflammatory diseases: a randomized clinical trial [18] 76.5 Effect of therapeutic drug monitoring vs standard therapy during infliximab induction on disease remission in patients with chronic immune-mediated inflammatory diseases: a randomized clinical trial [19] 72.In the final round, agreement percentages on topic inclusion are shown in the third column.Out of 20 topics, 15 were agreed upon in the first round.An additional 10 out of the remaining 15 were included in the second round.Three major reasons emerged from the panel's explanations for topic inclusion: the most common reason was that the topic had been published within the last 10 years; another significant reason was that the topic closely aligned with the objectives for developing our (systematic review of the literature) SRL; and the final reason was that the topic addressed an area previously overlooked, filling a recognized gap in the research.Table 5 shows an in-depth description of the articles we decided to use.   ) or the original formulation, this observation held true [13].A study [13] shows that measuring the lowest levels of infliximab in the blood at weeks six and 14 can tell us a lot about how likely it is that we will see clinical and endoscopic remission at weeks 30 and 54.Incorporating trough levels with markers of inflammation, such as fecal calprotectin or C-reactive protein (CRP), greatly improved the accuracy of predicting long-term remission outcomes [13].

Author
The SPARE trial, as reported by Louis et al., found that patients who stopped infliximab while on combination therapy had a higher risk of relapse compared to those who either continued on the combination or switched to infliximab monotherapy [14].This study examined patient characteristics that can help predict a higher likelihood of relapse and treatment failure.Interestingly, a significant number of patients who experienced a relapse showed a rapid response to infliximab retreatment without significantly affecting the overall duration of remission over a span of two years [14].It is important to consider various factors, such as patient preferences, clinical profiles, and broader health policy and economic contexts, when making decisions about treatment scaling down [14].
Louie et al. talked about the results of a study that looked into how well VE303, a specific mix of eight Clostridia strains, stopped Clostridium difficile infection (CDI) [17].A double-blind, placebo-controlled randomized controlled trial (RCT) conducted the study.This groundbreaking study showcased the effectiveness of VE303, making it the first documented case of a specific bacterial consortium proving its therapeutic benefits in a clinical setting [17].During the eight-week primary efficacy period, the use of highdose VE303 proved to be highly effective in preventing CDI recurrence in high-risk individuals.It is worth noting that all recurrences happened within the first 11 days, indicating swift colonization by VE303 strains and the restoration of gut microbiota [17].The observed effect showed long-lasting results, as the majority of participants continued to experience the benefits up to week 24 [17].
Syversen et al. emphasized the advantages of proactive therapeutic drug monitoring (TDM) in patients with immune-mediated inflammatory diseases who are on maintenance therapy with infliximab.They found that this approach helps to maintain disease control more effectively compared to treatment without TDM [18,19].However, another study by the same group found that initiating infliximab treatment did not significantly impact clinical remission rates with proactive TDM.This suggests that routine TDM might not be essential in the early stages of treatment for improving remission rates [18,19].
Schreiber et al.'s RCT demonstrated that subcutaneous (SC) CT-P13 is just as effective as the intravenous (IV) form in treating active IBD [20].Whether starting with a post-dose loading or switching from IV at week 30, the SC formulation consistently maintained infliximab trough levels above the therapeutic threshold throughout the study [20].The efficacy and safety profiles remained consistent for patients who continued subcutaneous (SC) treatment after receiving an intravenous (IV) dose loading, as well as for those who switched from IV to SC at week 30.This supports the use of the SC formulation as a viable and effective option for treating inflammatory bowel disease (IBD) [20].
In both the CD and ulcerative colitis (UC) groups, Jörgensen et al. evaluated the NOR-SWITCH trials and found no significant differences in effectiveness, safety, or immunogenicity between patients who received IFX and those who received CT-P13 [21].These findings provide support for the clinical suggestion of transitioning from the original to the biosimilar infliximab in patients with IBD [21].
D'Haens et al. found no advantage in adjusting the dose of IFX for active CD based on a combination of symptoms, biomarkers, and serum concentrations [22].This result highlights the difficulties of carrying out pure TDM trials, especially when biologic dose escalation is a common practice in clinical settings [22].Meanwhile, Vande Casteele and colleagues discovered that certain levels of IFX and antibodies to infliximab (ATI) are associated with CD remission.This emphasizes the importance of conducting more research on how ATI affects the effectiveness of IFX and finding ways to minimize its development [23].This extensive body of research highlights the importance of continuous investigations and practical applications in improving IFX treatment strategies for IBD [23].

Limitations
Genetic diversity and environmental factors: These factors can influence the response to IFX.Studies may not always account for these factors, potentially affecting the generalizability of the findings.
Patient adherence and real-world effectiveness: Clinical trial settings often have higher patient adherence rates than real-world settings.The effectiveness of IFX in routine clinical practice may differ from that observed in controlled trial environments.
Reporting of adverse effects: Inconsistent reporting of adverse effects and side effects across studies can lead to an incomplete understanding of the safety profile of infliximab.

Conclusions
In conclusion, our systematic review of current literature highlights the nuanced role of IFX in treating IBD.Studies consistently show that serum infliximab trough levels, along with markers of inflammation, are predictive of long-term remission, providing valuable insights for clinical decision-making.The SPARE trial underscores the risks of discontinuing IFX in patients on combination therapy, emphasizing the importance of individualized treatment plans.The innovative use of VE303, a bacterial consortium, marks a significant advancement in preventing Clostridium difficile infection, showcasing the potential of microbiota-targeted therapies.While proactive TDM shows benefits in maintenance therapy, its role during the induction phase remains debatable.The non-inferiority of subcutaneous CT-P13 compared to intravenous formulations offers flexibility in treatment administration without compromising efficacy or safety.The NOR-SWITCH trials further validate the interchangeability of original and biosimilar IFX formulations.Despite these advancements, the challenge of optimizing IFX dosing strategies persists, particularly in the context of antidrug antibodies.Continued research is essential to refine these strategies and enhance patient outcomes in IBD management.

FIGURE 1 :
FIGURE 1: PRISMA diagram PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

TABLE 5 :Figure 2
Figure 2 presents the Cochrane risk of bias tool for randomized controlled trials.

FIGURE 2 :
FIGURE 2: Cochrane risk of bias tool

TABLE 4 : Questionnaire topics
* Strikethrough: topics that remained excluded after the last Delphi round.